Transition Metal-Catalyzed Couplings in Process Chemistry: Case Studies from the Pharmaceutical Industry

406 Pages·2013·5.779 MB·English

by  Javier Magano, Joshua R. Dunetz(eds.)

Editedby
JavierMaganoand
JoshuaR.Dunetz
TransitionMetal-Catalyzed
CouplingsinProcess
Chemistry
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Edited by Javier Magano and Joshua R. Dunetz
Transition Metal-Catalyzed Couplings
in Process Chemistry
Case Studies from the Pharmaceutical Industry
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VII
Contents
Foreword1 XV
Foreword2 XVII
Foreword3 XIX
ListofContributors XXIII
Introduction XXIX
ListofAbbreviations XXXIII
1 Copper-CatalyzedCouplingforaGreenProcess 1
DavidJ.AgerandJohannesG.deVries
1.1 Introduction 1
1.2 SynthesisofAminoAcid14 4
1.2.1 AsymmetricHydrogenationApproach 4
1.2.2 EnzymaticApproaches 5
1.3 Copper-CatalyzedCyclization 6
1.3.1 C–NBondFormation 6
1.3.2 INDAC(1)Synthesis 8
1.4 Sustainability 10
1.5 Summary 10
References 11
2 ExperienceswithNegishiCouplingsonTechnicalScaleinEarly
Development 15
MuratAcemoglu,MarkusBaenziger,ChristophM.Krell,
andWolfgangMarterer
2.1 Introduction 15
2.2 SynthesisofLBT613viaPd-CatalyzedNegishi
Coupling 16
2.3 ElaborationofaNegishiCouplingintheSynthesisof
PDE472 19
2.4 Ni-CatalyzedNegishiCouplingwithCatalyticAmounts
ofZnCl 21
2
2.5 Conclusions 22
References 23
VIII Contents
3 DevelopingPalladium-CatalyzedArylationsofCarbonyl-Activated
C–HBonds 25
CarlA.BusaccaandChrisH.Senanayake
3.1 Introduction 25
3.2 SuzukiApproachtoSideChainInstallation 26
3.3 ArylationofCarbonyl-ActivatedC–HBonds 30
3.4 PdPurgingfromAPI 36
3.5 Conclusions 37
References 37
4 DevelopmentofaPracticalSynthesisofNaphthyridonep38
MAPKinaseInhibitorMK-0913 39
JohnY.L.Chung
4.1 Introduction 39
4.2 MedicinalChemistryApproachto1 40
4.3 ResultsandDiscussion 42
4.3.1 ADCRouteto21 42
4.3.2 TandemHeck–LactamizationRouteto23 47
4.3.3 Suzuki–MiyauraCoupling 48
4.3.4 PreparationofGrignard22forEndgameCouplings 49
4.3.5 CouplingofOrganomagnesium22andNaphthyridones19–21 50
4.4 Conclusions 54
References 54
5 PracticalSynthesisofaCathepsinSInhibitor 57
XiaohuDeng,NeelakandhaS.Mani,andJimmyLiang
5.1 Introduction 57
5.2 SyntheticStrategy 59
5.3 SynthesesofBuildingBlocks 59
5.4 SonogashiraCouplingandInitialPurificationof1 63
5.5 SaltSelection 65
5.6 Conclusions 70
References 70
6 C–NCouplingChemistryasaMeanstoAchieveaComplicatedMolecular
Architecture:theAR-A2CaseStory 73
Hans-Ju€rgenFedersel,MartinHedberg,FredrikR.Qvarnstr€om,andWeiTian
6.1 ANovelChemicalEntity 73
6.2 EvaluationofSyntheticPathways:FindingtheBestRoute 73
6.3 EnablingC–NCouplingbyDefiningtheReactionSpace 76
6.3.1 FirstExperiences 76
6.3.2 SetbacksandProblemSolutions 78
6.3.3 ScopingOutKeyParametersforBestReactionPerformance 79
6.3.4 LigandScreening 79
6.3.5 FindingtheBestBase 80
Contents IX
6.3.6 OptimizingtheLigand/MetalRatio 81
6.3.7 TemperatureEffect 82
6.3.8 OptimizingtheCatalystLoading 82
6.4 FromSynthesistoProcess 83
6.4.1 DemonstrationonScale 83
6.4.2 EnvironmentalPerformance 85
6.4.3 ImpurityTracking 86
6.5 ConcludingRemarks 88
References 88
7 ProcessDevelopmentandScale-upofPF-03941275,aNovel
Antibiotic 91
KevinE.HenegarandTimothyA.Johnson
7.1 Introduction 91
7.2 MedicinalChemistrySynthesisofPF-03941275 91
7.3 Synthesisof5-Bromo-2,4-difluorobenzaldehyde(1) 93
7.4 SynthesisofAmine3 93
7.5 MiyauraBorylationReaction 95
7.6 Suzuki–MiyauraCoupling 97
7.7 BarbituricAcidCoupling 101
7.8 ChlorinationandAPIIsolation 101
7.9 Conclusions 104
References 104
8 DevelopmentofaPracticalNegishiCouplingProcessforthe
ManufacturingofBILB1941,anHCVPolymeraseInhibitor 105
BruceZ.Lu,GuishengLi,FrankRoschangar,AzadHossain,RolfHerter,
VittorioFarina,andChrisH.Senanayake
8.1 IntroductionandBackground 105
8.2 StilleCoupling 107
8.3 SuzukiCoupling 107
8.4 NegishiCoupling 109
8.4.1 InitialInvestigation 109
8.4.2 NegishiCouplingOptimization 110
8.4.3 NegishiCouplingProcessScale-up 118
8.5 ComparisonofThreeCouplingProcesses 119
References 119
9 ApplicationofaRhodium-Catalyzed,Asymmetric1,4-Additiontothe
Kilogram-ScaleManufactureofaPharmaceuticalIntermediate 121
AlexandraParker
9.1 Introduction 121
9.2 EarlyDevelopment 122
9.3 ProcessOptimization 126
9.3.1 Manufacturability 127
X Contents
9.3.2 RhodiumRemoval 129
9.4 ProcessScale-up 131
9.5 RecentDevelopments 133
9.6 Conclusions 133
References 134
10 Copper-CatalyzedC–NCouplingonLargeScale:AnIndustrial
CaseStudy 135
AriannaRibecaiandPaoloStabile
10.1 Introduction 135
10.2 ProcessDevelopmentoftheC–NBondFormation 137
10.3 ChoiceofCatalyticSystem 140
10.4 ChoiceofBase:InorganicVersusOrganic 141
10.5 ChoiceofSolvent 142
10.6 OptimizedConditionsforC–NBondFormationto1 142
10.7 PurgingResidualCopperfrom1 143
10.8 Conclusions 144
References 144
11 DevelopmentofaHighlyEfficientRegio-andStereoselective
HeckReactionfortheLarge-ScaleManufacture
ofana4b2NNRAgonist 147
PerRyberg
11.1 Introduction 147
11.2 ProcessOptimization 149
11.2.1 SelectivityintheHeckReaction 149
11.2.2 IdentificationofSelectiveConditionsfortheHeckCoupling 149
11.2.3 InvestigationoftheMechanismoftheHeckStep 152
11.2.4 IdentificationofaSolutiontothePdMirrorProblem 153
11.2.5 DevelopmentofaBackupMethodforResidualPdRemoval 156
11.2.6 EffectofWaterontheReaction 157
11.2.7 DevelopmentofaSemicontinuousProcessBasedonCatalyst
Recycling 159
11.2.8 ApplicationonLargeScale 160
11.3 Conclusions 162
References 162
12 CommercialDevelopmentofAxitinib(AG-013736):Optimizationofa
ConvergentPd-CatalyzedCouplingAssemblyandSolidForm
Challenges 165
RobertA.Singer
12.1 Introduction 165
12.2 First-GenerationSynthesisofAxitinib 165
12.3 EarlyProcessResearchandDevelopment 167
12.4 CommercialRouteDevelopment 169